Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle

Abstract

Infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system. Recurrent ocular shedding can lead to corneal scarring and vision loss making HSV-1 a leading cause of corneal blindness due to an infectious agent. The primary site of HSV-1 latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During latency, the latency-associated transcript (LAT) is abundantly expressed. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. A novel transcript within LAT coding sequences (AL3) and small nonprotein coding RNAs are also expressed in trigeminal ganglia of latently infected mice. In this review, an update of viral factors that are expressed during latency and their potential roles in regulating the latency-reactivation cycle is discussed.

Figure 1

Steps in the latency-reactivation cycle of HSV-1. For details, see the text.

Figure 2

Location of genes within the HSV-1 repeats. (a) U_L and U_S denote the unique sequences of the long (L) and short (S) components of the genome. The boxes depict repeat sequences. (b) Transcription map of the repeat region. Location and orientation of LAT [114, 115], ICP0, γ134.5 [116, 117], ORFP [118], L/STs [119] are indicated by solid lines. Partially mapped transcripts (αX and βX) are denoted by dashed arrows [120, 121]. (c) The LAT promoter contains numerous cis-acting sites that can be bound by cellular transcription factors. Binding of ICP4 to the ICP4 binding site in the LAT promoter inhibits promoter activity [107]. In transient transfection assays, the LAT promoter can be divided into a strong promoter (LAP1) and a weaker promoter (LAP2) [99, 100]. For details of transcripts encoded by LAT, see Figure 3.

Figure 3

Schematic of factors encoded within the LAT locus. (a) Schematic of genes within the long repeats that contain the LAT locus. The large arrow indicates the primary LAT transcript. The solid rectangle represents the very stable 2 kb LAT intron. The start of LAT transcription is indicated by the arrow at +1 (genomic nucleotide 118801). Several restriction enzyme sites and the relative locations of the ICP0 and ICP34.5 transcripts are shown for reference. The locations of the 6 micro-RNAs (miR-H1-6) that are located within the 8.3 kb LAT [136] are shown. (b) Partial restriction map of LAT and position of LAT open reading frames (L1-8) within the first 1.5 Kb of strain McKrae LAT coding sequences, which were based on previous studies [137]. The numbering system of the ORFs was consistent with a previous study [137]. Only the ORFs with at least 30 amino acids are shown (the number of amino acids in each ORF is denoted by the numbers in brackets). Open circles denote the position of two LAT small RNAs that are encoded within the first 1.5 kb LAT coding sequences [138]. Positions of UOL transcript, AL transcript, and ORFs located on the opposite strand of LAT (AL2 and AL3) are shown. The numbers of amino acids of AL2 and AL3 are in brackets. Nucleotide positions relative to the start of LAT transcription are not shown in parenthesis. Numbers in parentheses represent HSV-1 nucleotide positions.